Visual Abstract

Visual Abstract
Visual Abstract.
View largeDownload slide
Keywords:
Kidney transplantation, Chronic allograft injury, Fibrosis, Lysophosphatidic acid, Autotaxin

Background: Tissue fibrosis is the final common phase of chronic allograft injury, the leading cause of late graft loss in kidney transplantation. Preclinical evidence points to the involvement of lysophosphatidic acid (LPA), a bioactive phospholipid, in the development of renal fibrosis. Objectives: We assessed whether treatment with an orally available inhibitor of autotaxin (ATXi), the main LPA-producing enzyme, could slow the progression of chronic allograft injury in a fully major histocompatibility complex-mismatched rat kidney transplant model and compared its effects with those of the angiotensin-converting enzyme inhibitor lisinopril. Methods: Kidney allograft recipients were given ciclosporin for the first 15 postoperative days to prevent early acute rejection. Thereafter, they received either no treatment or ATXi or lisinopril and were followed for 180 days after transplantation. Results: Renal LPA levels were increased in allograft rats, providing the rationale for using ATXi in this model. Chronic treatment with ATXi or lisinopril limited progressive proteinuria and ameliorated tubulointerstitial fibrosis compared with allograft rats, although the effects were more robust under ATX inhibition. The administration of ATXi, but not lisinopril, attenuated systemic hypertension, reduced intragraft T cell infiltration, and eventually improved renal graft survival. Conclusions: In summary, ATXi had protective effects on indices of chronic allograft injury and could be of therapeutic add-on value in the kidney transplant setting. Notably, an ATX inhibitor is currently being investigated in 2 large phase 3 studies in idiopathic pulmonary fibrosis, underscoring the clinical relevance of our findings.

Keywords:
Kidney transplantation, Chronic allograft injury, Fibrosis, Lysophosphatidic acid, Autotaxin
1.
Solez K, Colvin RB, Racusen LC, Sis B, Halloran PF, Birk PE, et al. Banff ’05 Meeting -Report: differential diagnosis of chronic -allograft injury and elimination of chronic -allograft nephropathy (‘CAN’).
Am J Transplant
. 2007 Mar;7(3):518–26.
2.
Lodhi SA, Lamb KE, Meier-Kriesche HU. Solid organ allograft survival improvement in the United States: the long-term does not mirror the dramatic short-term success.
Am J Transplant
. 2011 Jun;11(6):1226–35.
3.
Joosten SA, Sijpkens YW, van Kooten C, Paul LC. Chronic renal allograft rejection: pathophysiologic considerations.
Kidney Int
. 2005 Jul;68(1):1–13.
4.
Boor P, Floege J. Renal allograft fibrosis: biology and therapeutic targets.
Am J Transplant
. 2015 Apr;15(4):863–86.
5.
Shrestha BM, Haylor J. Biological pathways and potential targets for prevention and therapy of chronic allograft nephropathy.
BioMed Res Int
. 2014;2014:482438.
6.
Amuchastegui SC, Azzollini N, Mister M, Pezzotta A, Perico N, Remuzzi G. Chronic allograft nephropathy in the rat is improved by angiotensin II receptor blockade but not by calcium channel antagonism.
J Am Soc Nephrol
. 1998 Oct;9(10):1948–55.
7.
Ziai F, Nagano H, Kusaka M, Coito AJ, Troy JL, Nadeau KC, et al. Renal allograft protection with losartan in Fisher–Lewis rats: hemodynamics, macrophages, and cytokines.
Kidney Int
. 2000 Jun;57(6):2618–25.
8.
Noris M, Azzollini N, Pezzotta A, Mister M, Benigni A, Marchetti G, et al. Combined treatment with mycophenolate mofetil and an angiotensin II receptor antagonist fully protects from chronic rejection in a rat model of renal allograft.
J Am Soc Nephrol
. 2001 Sep;12(9):1937–46.
9.
Noris M, Mister M, Pezzotta A, Azzollini N, Cassis P, Benigni A, et al. ACE inhibition limits chronic injury of kidney transplant even with treatment started when lesions are established.
Kidney Int
. 2003 Dec;64(6):2253–61.
10.
Cravedi P, Perico N, Remuzzi G. Non-immune interventions to protect kidney allografts in the long term.
Kidney Int Suppl
. 2010 Dec;78(119):S71–5.
11.
Salzberg DJ. Is RAS blockade routinely indicated in hypertensive kidney transplant patients?
Curr Hypertens Rep
. 2007 Nov;9(5):422–9.
12.
Aikawa S, Hashimoto T, Kano K, Aoki J. Lysophosphatidic acid as a lipid mediator with multiple biological actions.
J Biochem
. 2015 Feb;157(2):81–9.
13.
Nikolaou A, Kokotou MG, Limnios D, Psarra A, Kokotos G. Autotaxin inhibitors: a patent review (2012-2016). Expert Opin Ther Pat. 2017 Jul;27(7):815–29.
14.
Cholia RP, Nayyar H, Kumar R, Mantha AK. Understanding the Multifaceted Role of Ectonucleotide Pyrophosphatase/Phosphodiesterase 2 (ENPP2) and its Altered Behaviour in Human Diseases.
Curr Mol Med
. 2015;15(10):932–43.
15.
Tager AM, LaCamera P, Shea BS, Campanella GS, Selman M, Zhao Z, et al. The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak.
Nat Med
. 2008 Jan;14(1):45–54.
16.
Oikonomou N, Mouratis MA, Tzouvelekis A, Kaffe E, Valavanis C, Vilaras G, et al. Pulmonary autotaxin expression contributes to the pathogenesis of pulmonary fibrosis.
Am J Respir Cell Mol Biol
. 2012 Nov;47(5):566–74.
17.
Pradère JP, Klein J, Grès S, Guigné C, Neau E, Valet P, et al. LPA1 receptor activation promotes renal interstitial fibrosis.
J Am Soc Nephrol
. 2007 Dec;18(12):3110–8.
18.
Pradère JP, Gonzalez J, Klein J, Valet P, Grès S, Salant D, et al. Lysophosphatidic acid and renal fibrosis.
Biochim Biophys Acta
. 2008 Sep;1781(9):582–7.
19.
Sakai N, Chun J, Duffield JS, Lagares D, Wada T, Luster AD, et al. Lysophosphatidic acid signaling through its receptor initiates profibrotic epithelial cell fibroblast communication mediated by epithelial cell derived connective tissue growth factor.
Kidney Int
. 2017 Mar;91(3):628–41.
20.
Sakai N, Bain G, Nakamura M, Miyake T, Kamikawa Y, Sagara A, et al. Autotaxin promotes renal interstititial fibrosis by inducing vascular leak and fibroblast accumulation. J Am Soc Nephrol 2016 Nov;27:143A (TH-PO213).
21.
Prunotto M, Moll S, Chatziantoniou C, Raab S, Badi L, Ullmer C. Decreased inflammation and fibrosis in experimental model of crescentic glomerulonephritis. J Am Soc Nephrol 2016 Nov;27:127A (TH-PO143).
22.
Bain G, Shannon KE, Huang F, Darlington J, Goulet L, Prodanovich P, et al. Selective Inhibition of Autotaxin Is Efficacious in Mouse Models of Liver Fibrosis.
J Pharmacol Exp Ther
. 2017 Jan;360(1):1–13.
23.
Castelino FV, Bain G, Pace VA, Black KE, George L, Probst CK, et al. An Autotaxin/Lysophosphatidic Acid/Interleukin-6 Amplification Loop Drives Scleroderma Fibrosis.
Arthritis Rheumatol
. 2016 Dec;68(12):2964–74.
24.
Cao P, Aoki Y, Badri L, Walker NM, Manning CM, Lagstein A, et al. Autocrine lysophosphatidic acid signaling activates β-catenin and promotes lung allograft fibrosis.
J Clin Invest
. 2017 Apr;127(4):1517–30.
25.
Benigni A, Tomasoni S, Turka LA, Longaretti L, Zentilin L, Mister M, et al. Adeno-associated virus-mediated CTLA4Ig gene transfer protects MHC-mismatched renal allografts from chronic rejection.
J Am Soc Nephrol
. 2006 Jun;17(6):1665–72.
26.
Gierse J, Thorarensen A, Beltey K, Bradshaw-Pierce E, Cortes-Burgos L, Hall T, et al. A novel autotaxin inhibitor reduces lysophosphatidic acid levels in plasma and the site of inflammation.
J Pharmacol Exp Ther
. 2010 Jul;334(1):310–7.
27.
Kramer CY. Extension of multiple range tests to group means with unequal numbers of replications.
Biometrics
. 1956;12(3):307–10.
28.
Solini S, Aiello S, Cassis P, Scudeletti P, Azzollini N, Mister M, et al. Prolonged cold ischemia accelerates cellular and humoral chronic rejection in a rat model of kidney allotransplantation.
Transpl Int
. 2012 Mar;25(3):347–56.
29.
Cassis P, Gallon L, Benigni A, Mister M, Pezzotta A, Solini S, et al. Erythropoietin, but not the correction of anemia alone, protects from chronic kidney allograft injury.
Kidney Int
. 2012 May;81(9):903–18.
30.
Tokumura A, Fukuzawa K, Tsukatani H. Effects of synthetic and natural lysophosphatidic acids on the arterial blood pressure of different animal species.
Lipids
. 1978 Aug;13(8):572–4.
31.
Tigyi G, Hong L, Yakubu M, Parfenova H, Shibata M, Leffler CW. Lysophosphatidic acid alters cerebrovascular reactivity in piglets.
Am J Physiol
. 1995 May;268(5 Pt 2):H2048–55.
32.
Xu K, Ma L, Li Y, Wang F, Zheng GY, Sun Z, et al. Genetic and Functional Evidence Supports LPAR1 as a Susceptibility Gene for Hypertension.
Hypertension
. 2015 Sep;66(3):641–6.
33.
Zhang MZ, Wang X, Yang H, Fogo AB, Murphy BJ, Kaltenbach R, et al. Lysophosphatidic Acid Receptor Antagonism Protects against Diabetic Nephropathy in a Type 2 Diabetic Model.
J Am Soc Nephrol
. 2017 Nov;28(11):3300–11.
34.
Li HY, Oh YS, Choi JW, Jung JY, Jun HS. Blocking lysophosphatidic acid receptor 1 signaling inhibits diabetic nephropathy in db/db mice.
Kidney Int
. 2017 Jun;91(6):1362–73.
35.
Aoki J, Taira A, Takanezawa Y, Kishi Y, Hama K, Kishimoto T, et al. Serum lysophosphatidic acid is produced through diverse phospholipase pathways.
J Biol Chem
. 2002 Dec;277(50):48737–44.
36.
Hozumi H, Hokari R, Kurihara C, Narimatsu K, Sato H, Sato S, et al. Involvement of autotaxin/lysophospholipase D expression in intestinal vessels in aggravation of intestinal damage through lymphocyte migration.
Lab Invest
. 2013 May;93(5):508–19.
37.
Zhang Y, Chen YC, Krummel MF, Rosen SD. Autotaxin through lysophosphatidic acid stimulates polarization, motility, and transendothelial migration of naive T cells.
J Immunol
. 2012 Oct;189(8):3914–24.
38.
Bai Z, Cai L, Umemoto E, Takeda A, Tohya K, Komai Y, et al. Constitutive lymphocyte transmigration across the basal lamina of high endothelial venules is regulated by the autotaxin/lysophosphatidic acid axis.
J Immunol
. 2013 Mar;190(5):2036–48.
39.
Knowlden S, Georas SN. The autotaxin-LPA axis emerges as a novel regulator of lymphocyte homing and inflammation.
J Immunol
. 2014 Feb;192(3):851–7.
40.
Remuzzi G, Bertani T. Pathophysiology of progressive nephropathies.
N Engl J Med
. 1998 Nov;339(20):1448–56.
41.
Rodriguez-Iturbe B, Pons H, Johnson RJ. Role of the Immune System in Hypertension.
Physiol Rev
. 2017 Jul;97(3):1127–64.
42.
Rodríguez-Iturbe B, Quiroz Y, Ferrebuz A, Parra G, Vaziri ND. Evolution of renal interstitial inflammation and NF-kappaB activation in spontaneously hypertensive rats.
Am J Nephrol
. 2004 Nov-Dec;24(6):587–94.
43.
Rodríguez-Iturbe B, Quiroz Y, Nava M, Bonet L, Chávez M, Herrera-Acosta J, et al. Reduction of renal immune cell infiltration results in blood pressure control in genetically hypertensive rats.
Am J Physiol Renal Physiol
. 2002 Feb;282(2):F191–201.
44.
Maher TM, van der Aar EM, Van de Steen O, Allamassey L, Desrivot J, Dupont S, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1690, a novel autotaxin inhibitor, to treat idiopathic pulmonary fibrosis (FLORA): a phase 2a randomised placebo-controlled trial.
Lancet Respir Med
. 2018 Aug;6(8):627–35.
© 2019 S. Karger AG, Basel
2019
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.